Prostate cancer is the most common cancer and the second leading cause of cancer-related deaths in men in the United States. Patients with localized disease may be treated with surgery or radiation, whereas the treatment for patients with metastatic disease is purely palliative. Gene therapy targeting specific abnormalities is being actively evaluated for the treatment of prostate cancers. We have documented that adenovirus-mediated delivery of melanoma differentiation associated gene-7/interleukin-24 (mda-7/IL-24), a secreted cytokine having cancer-selective apoptosis-inducing property, profoundly inhibits growth of prostate cancer cells both in vitro and in vivo. However, forced overexpression of anti-apoptotic protein Bcl-2 or Bcl-xL renders prostate cancer cells resistant to Ad.mda-7. We constructed a conditionally replication competent adenovirus in which the expression of adenoviral E1A gene, necessary for replication, is driven by the cancer-specific promoter of the progression elevated gene-3 (PEG-3) and which simultaneously expresses mda-7/IL-24 in the E3 region of the adenovirus (Ad.PEG-E1A-mda-7) thereby mediating robust production of this cytokine as a function of adenoviral replication. Infection of Ad.PEG-E1A-mda-7 in normal prostate epithelial cells and prostate cancer cells, including Bcl-2 or Bcl-xL overexpressing cells such as Du-145-Bcl-xL, PC-3-Bcl-xL and LNCaP-Bcl-2, confirmed cancer cell selective adenoviral replication, mda-7/IL-24 expression, growth inhibition and apoptosis induction. Injecting Ad.PEG-E1A-mda-7 into xenografts derived from Du-145-Bcl-xL cells in athymic nude mice completely eradicated not only the primary tumor but also distant tumors (established on the opposite flank of the animal) thereby implementing a cure. Overexpression of Bcl-2 or Bcl-xL is frequently observed in patient-derived prostate cancer samples and is associated with resistance to conventional therapy. Our dual cancer-specific targeting strategy facilitated the eradication of both primary and distant resistant prostate cancers thus demonstrating potential for translational application of this strategy for treating terminal prostate cancer patients.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA